Biology subjects

Delignat-Lavaud, B.

Publications and source records attributed to Delignat-Lavaud, B..

8 recordsLinked to original sources

bioRxiv2024

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer's Disease

The symptomatology of Alzheimers disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.

neuroscience↗

bioRxiv2023

Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and psychiatric disease

The dopamine transporter (DAT) plays a crucial role in regulating the brains dopamine (DA) homeostasis. Atypical DAT deficiency syndrome (DTSD) is a disease characterized by early-onset parkinsonism and comorbid psychiatric symptoms, but the pathobiological processes that link DAT dysfunction to both parkinsonism and psychiatric symptoms are unknown. Here, we present a genetic mouse model of atypical DTDS that expresses two coding DAT variants, DAT-I312F and DAT-D421N, derived from a patient diagnosed with ADHD and parkinsonism. Phenotypic characterization of the mutant mice revealed impaired DAT function and major homeostatic changes including increased ambient extracellular DA levels, decreased evoked DA release, and reduced expression of both tyrosine hydroxylase (TH) and of DA D1/D2 receptors. This was accompanied by diminished striatal dopaminergic axonal density and a psychomotor phenotype characterized by hyperactivity, enhanced exploratory activity, and pronounced clasping. Importantly, both amphetamine and anticholinergic treatment ameliorated aberrant hyperlocomotion in the mice. Summarized, by replicating core aspects of the patients phenotype, the mouse model not only provides insights into the mechanisms underlying atypical DTDS but also underlines the broad relevance of DA deficits for understanding the co-morbidity between neuropsychiatric diseases and parkinsonism. ONE SENTENCE SUMMARYIn a new mouse disease model, we explore the behavioral consequences and dopaminergic dysfunction that arise from patient-derived mutations in the dopamine transporter associated with parkinsonism and co-morbid neuropsychiatric disease

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bioRxiv2021

Neurexins Regulate GABA Co-release by Dopamine Neurons

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions. HighlightsO_LIThe study provides the first direct evidence of the role of neurexins in dopaminergic neurons. C_LIO_LIThe synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals. C_LIO_LINeurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion. C_LIO_LIDeletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons. C_LI

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bioRxiv2021

The calcium sensor synaptotagmin-1 is critical for phasic axonal dopamine release in the striatum and mesencephalon, but is dispensable for basic motor behaviors in mice

In Parkinsons disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKODA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

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bioRxiv2021

Implication of synaptotagmins 4 and 7 in activity-dependent somatodendritic dopamine release

Dopamine (DA) neurons can release DA not just from axon terminals, but also from their somatodendritic (STD) compartment thought a mechanism that is still incompletely understood. Using voltammetry in mouse mesencephalic brain slices, we find that STD DA release has low capacity, is stable in response to electrical but not optogenetic train pulses and shows a calcium sensitivity that is comparable to that of axonal release. It is also strikingly more resilient compared to axonal release in a 6- hydroxydopamine model of Parkinsons disease plasticity. We find that the molecular mechanism of STD DA release differs from axonal release with regards to the implication of synaptotagmin (Syt) calcium sensors. While individual constitutive knock-out Syt4 and Syt7 is not sufficient to reduce STD DA release, removal of both isoforms reduces this release by ~50%, leaving axonal release unimpaired. Our works unveils clear differences in the mechanisms of STD and axonal DA release.

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bioRxiv2020

Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals

Chemical neurotransmission in the brain typically occurs through synapses, which are structurally and functionally defined as sites of close apposition between an axon terminal and a postsynaptic domain. Ultrastructural examinations of axon terminals established by monoamine neurons in the brain often failed to identify a similar tight pre- and postsynaptic coupling, giving rise to the concept of "diffuse" or "volume" transmission. Whether this results from intrinsic properties of such modulatory neurons remains undefined. Using an efficient co-culture model, we find that dopaminergic neurons establish an axonal arbor that is distinctive compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. Furthermore, while most dopaminergic varicosities express key proteins involved in exocytosis such as synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in a subset of dopaminergic terminals that are in proximity to a target cell. Irrespective of their structure, a majority of dopaminergic terminals were found to be active. Finally, we found that the presynaptic protein Nrxn-1SS4- and the postsynaptic protein NL-1AB, two major components involved in excitatory synapse formation, play a critical role in the formation of synapses by dopamine neurons. Taken together, our findings support the idea that dopamine neurons in the brain are endowed with a distinctive developmental program that leads them to adopt a fundamentally different mode of connectivity, compared to glutamatergic and GABAergic neurons involved in fast point-to-point signaling. SIGNIFICANCE STATEMENTMidbrain dopamine (DA) neurons regulate circuits controlling movement, motivation, and learning. The axonal connectivity of DA neurons is intriguing due to its hyperdense nature, with a particularly large number of release sites, most of which not adopting a classical synaptic structure. In this study, we provide new evidence highlighting the unique ability of DA neurons to establish a large and heterogeneous axonal arbor with terminals that, in striking contrast with glutamate and GABA neurons, actively avoid contact with the target cells. The majority of synaptic and non-synaptic terminals express proteins for exocytosis and are active. Finally, our finding suggests that, NL-1A+B and Nrxn-1SS4-, play a critical role in the formation of synapses by DA neurons.

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bioRxiv2020

Amphetamine Maintenance Therapy During Intermittent Cocaine Self-Administration in Rats: Reduction of Addiction-like Behavior is Associated with Attenuation of Psychomotor and Dopamine Sensitization

BackgroundD-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaines effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaines potency at the DAT. MethodsMale rats self-administered cocaine intermittently (5 minutes ON, 25 minutes OFF x 10) for 14 sessions, with or without concomitant D-amphetamine (5 mg/kg/day via s.c. osmotic minipump). In Experiment 1, psychomotor sensitization, responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed relapse were assessed. In Experiment 2, rats self-administered cocaine or saline intermittently, with or without D-amphetamine, and the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core was assessed using fast scan cyclic voltammetry ex vivo. ResultsIntA cocaine self-administration produced psychomotor sensitization, strong motivation to take and seek cocaine, and it increased cocaines potency at the DAT. The co-administration of D-amphetamine suppressed both the psychomotor sensitization and high motivation for cocaine produced by IntA experience, and also reversed sensitization of cocaines actions at the DAT, leaving baseline DAT function unchanged. ConclusionsTreatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

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bioRxiv2019

Vglut2 expression in dopamine neurons contributes to post-lesional striatal reinnervation

In Parkinsons disease, the most vulnerable neurons are found in the ventral tier of the substantia nigra (SN), while the adjacent dopamine (DA) neurons of the ventral tegmental area (VTA) are mostly spared. Although a significant subset of adult VTA DA neurons expresses Vglut2, a vesicular glutamate transporter, and release glutamate as a second neurotransmitter in the striatum, only very few adult SN DA neurons have this capacity. Previous work has demonstrated that lesions created by neurotoxins such as MPTP and 6-hydroxydopamine (6-OHDA) can upregulate the expression of Vglut2 in surviving DA neurons. Currently, the molecular mechanisms explaining the plasticity of Vglut2 expression in DA neurons are unknown, as are the physiological consequences for DA neuron function and survival. Here we aimed to characterize the developmental expression pattern of Vglut2 in DA neurons and the role of this transporter in post-lesional plasticity in these neurons. Using an intersectional genetic lineage-mapping approach, based on Vglut2-Cre and TH-Flpo drivers, we first found that more than 98% of DA neurons expressed Vglut2 at some point in their embryonic development. Expression of this transporter was detectable in most DA neurons until E11.5 and was found to be localized in developing axons. Moderate enhancement of VGLUT2 expression in primary DA neurons caused an increase in axonal arborization length. Compatible with a developmental role, constitutive deletion of Vglut2 caused a regional defect in TH-innervation of the dorsal striatum in E18.5 embryos. Moreover, using an in vitro neurotoxin model, we demonstrate that Vglut2 expression can be upregulated in post-lesional DA neurons by 2.5-fold, arguing that the developmental expression of Vglut2 in DA neurons can be reactivated at postnatal stages and contribute to post-lesional plasticity of dopaminergic axons. In support of this hypothesis, we find fewer mesostriatial dopaminergic projections in the striatum of conditional Vglut2 KO mice 7 weeks after a neurotoxic lesion, compared to control animals. Thus, we propose here that one of the functions of Vglut2 in adult DA neurons is to promote post-lesional recovery of meso-striatal axons.

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